Psilocybin Intervention for Veterans Overcoming Treatment-Resistant Depression (PIVOT)

A Multi-site Randomized Controlled Trial of Psilocybin for Treatment-Resistant Depression (TRD) in Veterans

The purpose of this multi-site randomized controlled trial is to evaluate the efficacy and risks of psilocybin for the treatment of depression in U.S. military Veterans with and without (±) concurrent posttraumatic stress disorder.

Study Overview

• Status: Not yet recruiting
• Conditions: Major Depression
• Intervention / Treatment: Drug: Psilocybin; Drug: Psilocybin

Detailed Description

Treatment-resistant depression (TRD) is a serious mental health problem in Veterans, frequently comorbid with post-traumatic stress disorder (PTSD), and in need of novel and effective treatments. Clinical studies have revealed antidepressant effects of psilocybin for depression in civilians, but less is known about its efficacy and safety in Veterans. Very limited data is available on the effects of psilocybin in the treatment of PTSD. Thus, it is important to evaluate the safety and efficacy of psilocybin in the treatment of TRD with and without PTSD among Veterans.

The purpose of this multi-site, double-blind, randomized controlled trial is to evaluate the efficacy and risks of psilocybin for the treatment of TRD in U.S. military Veterans with and without (±) concurrent PTSD. Eligible and consenting Veterans will two psilocybin dosing sessions along with preparation, administration, and integration psychological support provided by a facilitator. For the 1st psilocybin administration, participants will be randomized to one of two doses under blinded conditions. One month later, all participants will receive a 25mg dose at their 2nd psilocybin visit. Outcomes will be measured by an independent evaluator masked from all treatments at 2 and 4 weeks after each dosing session. Longer-term follow-up will be conducted over 6 months. Both expected and unanticipated adverse events will be collected by type, severity and relatedness to the study drug.

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Lori L Davis, MD AB; Phone Number: (205) 554-3819; Email: lori.davis@va.gov
• Study Contact Backup: Name: Anchal Ghera, MS; Phone Number: (205) 899-1273; Email: anchal.ghera@va.gov

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233-1927
      • Birmingham VA Medical Center, Birmingham, AL
      • Contact: Lori L Davis, MD AB; Phone Number: (205) 554-3819; Email: lori.davis@va.gov
      • Principal Investigator: Lori Lynne Davis, MD AB
      • Contact: Anchal Ghera, MS; Phone Number: (205) 899-1273; Email: anchal.ghera@va.gov
    • Tuscaloosa, Alabama, United States, 35404-5015
      • Tuscaloosa VA Medical Center, Tuscaloosa, AL
      • Contact: Patricia Pilkinton, MD; Phone Number: 205-554-2000; Email: patricia.pilkinton@va.gov
      • Contact: Kaleb Murry, MS; Phone Number: 2055542000; Email: kaleb.murry@va.gov
  • Oregon
    • Portland, Oregon, United States, 97207-2964
      • VA Portland Health Care System, Portland, OR
      • Contact: Christopher Stauffer, MD; Email: christopher.stauffer@va.gov
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4551
      • Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
      • Contact: Michael Thase, MD; Email: michael.thase@va.gov
  • Washington
    • Seattle, Washington, United States, 98108-1532
      • VA Puget Sound Health Care System Seattle Division, Seattle, WA
      • Contact: Rebecca Hendrickson, MD; Email: rebecca.hendrickson@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Veteran of the U.S. military who is English-speaking
• Signed informed consent and HIPAA
• Adults </= 75 years of age
• Meets DSM-5 criteria for current major depressive episode (MDE)
• MADRS >/= 20 at baseline
• Failure to respond satisfactorily to >/= 2 antidepressant treatments for >/= 8 weeks, including >/= 2 weeks at an adequate dose (>/= 50% of the FDA-approved uppermost dose) for major depression. Augmentation with a medication for depression (e.g., neuroleptics, lithium, levothyroxine) is considered a separate course of treatment.
• If applicable, concurrent & permitted antidepressants must be at stable doses for >/= 4 weeks prior to baseline (see allowed & prohibited medication list)
• Participants of child-bearing potential must have negative pregnancy test & agree to adhere to a medically acceptable method of birth control during the study
• Has a responsible adult who will provide transportation to the participant's home or place of lodging on the days of psilocybin administration

Exclusion Criteria:

Exclusion Criteria:

• Lifetime bipolar, schizophrenia spectrum, or other psychotic disorders
• First-degree relative with history of bipolar I, schizophrenia spectrum or other psychotic disorder
• Presence of psychotic symptoms (e.g., MDE with psychotic symptoms)
• Sedative-hypnotic, stimulant, inhalant and/or opioid use disorder within past 6 months (lifetime substance use disorder is allowed at the discretion of the LSI)
• Severe alcohol and/or cannabis use disorder within the past 6 months (mild or moderate alcohol and/or cannabis use is allowed at the discretion of the LSI)
• Lifetime hallucinogen persisting perception or hallucinogen use disorders
• Use of psilocybin, ayahuasca, mescaline, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), peyote, or 3,4-methylenedioxymethamphetamine (MDMA) within past 6 months
• Participant agrees to not use psychedelics (listed above) during the study, except as prescribed by the study protocol
• Taking prohibited medication within 2 weeks of baseline (see allowed and prohibited concomitant medication list)
• History of severe traumatic brain injury (TBI)
• Diagnosis of dementia or related progressive neurocognitive disorder
• Suicidal ideation/behavior Type 4 or Type 5 intensity on C-SSRS within past 6 months of baseline
• Psychiatric inpatient treatment within past 3 months of baseline
• Treatment with electroconvulsive therapy, deep brain stimulation, vagus nerve stimulation, or transcranial magnetic stimulation within 3 months of baseline
• Implanted central nervous system device
• Treatment with evidence-based psychotherapy (EBP) for MDD or PTSD within 2 weeks prior to baseline. If receiving EBP therapy, he/she must complete treatment at least 2 weeks prior to baseline. Other forms of non-EBP psychotherapy for MDD or PTSD are allowed to continue during the study period.
• Pregnancy or lactation, or anticipated pregnancy or breastfeeding during the active treatment phase
• History of myocardial infarction, congestive heart failure, diabetic ketoacidosis, brain cancer, stroke and/or severe cardiac disease
• Clinically significant cardiac, pulmonary, renal, liver and/or other medical disease that, in the opinion of the investigator, may contraindicate the use of psilocybin, interfere with the interpretation of study results and/or constitute a health risk for the participant if they take part in the study
• Seizure disorder, except for seizures due to fever or withdrawal from a substance
• Clinically significant hypertension (>160/95 mmHg), hypotension (<90/60 mmHg) tachycardia (>100 bpm at rest), QTc prolongation (>450 msec men; >470 msec women) or clinically significant arrhythmia on ECG
• Clinically significant abnormal laboratory results on chemistry panel, liver function tests, complete blood count, and/or thyroid stimulating hormone
• Positive urine drug screen for illicit drugs of abuse (except for THC) at screening or baseline
• Prior allergic, adverse reaction or adverse experience to a psilocybin formulation
• Litigating for disability income for a mental disorder outside the VA compensation and pension process

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; Psilocybin comparator dose	Drug: Psilocybin; Psilocybin comparator dose; Other Names: COMP360; Drug: Psilocybin; Psilocybin Intervention Dose; Other Names: COMP360
Experimental: Intervention; Psilocybin intervention dose	Drug: Psilocybin; Psilocybin comparator dose; Other Names: COMP360; Drug: Psilocybin; Psilocybin Intervention Dose; Other Names: COMP360

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montgomery-Asberg Rating Scale (MADRS)	10-item clinician-administered rating scale for depression. Scored 0 to 60; higher score indicates more severe symptomatology.	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Swiss Psychedelic Side Effects Inventory Overall Score	A clinician guided self-report form that has a list of effects pertaining to psychedelics; has the option to add other side effects (or expected effects) as desired and includes an open text field to provide additional details that are not captured in the inventory list. In addition to rating severity of the side effects, the SPSI captures impact, causality, timing and duration, and has a global rating on tolerability. Scoring: Calculate total scores for the number of side effects, severity, and impact by adding the relevant columns. Calculate total scores for the number of side effects, severity, and impact by adding the relevant columns. The overall score is calculated by subtracting total severity from total impact. The overall score represents the burden of side effects for that person within the specified timeframe.	one day

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinician-Administered PTSD Scale for DSM-5 - Revised	A 30-item interview used to rate the past-month PTSD severity in those participants diagnosed with PTSD by CAPS-5-R at baseline. Higher score (0 to 200) indicates higher PTSD severity.	one month
Hamilton Depression Rating Scale	A validated rater-administered measure of depression severity. The 17-item version yields a score of 0 to 50; higher score indicates more severe depression.	two weeks
Patient Health Questionnaire 9	A 9-item self-report measure designed to characterize severity of depression; has excellent psychometrics, total score range 0 to 27, higher = more severe.	two weeks
PTSD Checklist for DSM-5	A 20-item self-report of PTSD symptoms; score 0-80; higher=more severe. Only collected in those with PTSD diagnosis at baseline.	one month

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Lori Lynne Davis, MD AB, Birmingham VA Medical Center, Birmingham, AL

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): December 2, 2030
• Study Completion (Estimated): April 30, 2031

Study Registration Dates

• First Submitted: November 5, 2025
• First Submitted That Met QC Criteria: November 6, 2025
• First Posted (Actual): November 10, 2025

Study Record Updates

• Last Update Posted (Actual): November 10, 2025
• Last Update Submitted That Met QC Criteria: November 6, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: depression; veterans; post-traumatic stress disorder; psilocybin
• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Mental Disorders; Behavioral Symptoms; Mood Disorders; Stress Disorders, Traumatic; Depressive Disorder; Behavior; Depression; Depressive Disorder, Major; Stress Disorders, Post-Traumatic; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Indoles; Indole Alkaloids; Indolizidines; Indolizines; Tryptamines; Psilocybin
• Other Study ID Numbers: MHBC-002-25S

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data and a data dictionary will be shared pending required IRB approval, and if needed, a Data Use Agreement.
• IPD Sharing Time Frame: At the conclusion of the study after a data repository has been made operational.
• IPD Sharing Access Criteria: De-identified data of those participants who signed informed consent, to include baseline demographics and clinical characteristics, primary outcome measure over time, treatment assignment, secondary safety outcomes, and exploratory outcomes. Data will be available for 6 years after the closure of the main study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No